The landscape of epilepsy-related GATOR1 variants
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Baldassari, Sara | Picard, Fabienne | Verbeek, Nienke, E. | van Kempen, Marjan | Brilstra, Eva | Lesca, Gaetan | Conti, Valerio | Guerrini, Renzo | Bisulli, Francesca | Licchetta, Laura | Pippucci, Tommaso | Tinuper, Paolo | Hirsch, Edouard | de Saint Martin, Anne | Chelly, Jamel | Rudolf, Gabrielle | Chipaux, Mathilde | Ferrand-Sorbets, Sara | Dorfmüller, Georg | Sisodiya, Sanjay | Balestrini, Simona | Schoeler, Natasha | Hernandez-Hernandez, Laura | Krithika, S. | Oegema, Renske | Hagebeuk, Eveline | Gunning, Boudewijn | Deckers, Charles | Berghuis, Bianca | Wegner, Ilse | Niks, Erik | Jansen, Floor | Braun, Kees | de Jong, Danielle | Rubboli, Guido | Talvik, Inga | Sander, Valentin | Uldall, Peter | Jacquemont, Marie-Line | Nava, Caroline | Leguern, Eric, E. | Julia, Sophie | Gambardella, Antonio | D’orsi, Giuseppe | Crichiutti, Giovanni | Faivre, Laurence | Darmency, Véronique | Benova, Barbora | Krsek, Pavel | Biraben, Arnaud | Lebre, Anne | Jennesson, Mélanie | Sattar, Shifteh | Marchal, Cécile | Nordli, Douglas | Lindstrom, Kristin | Striano, Pasquale | Lomax, Lysa Boissé | Kiss, Courtney | Bartolomei, Fabrice | Lepine, Fabienne | Schoonjans, An-Sofie | Stouffs, Katrien | Jansen, Anna | Panagiotakaki, Eleni | Ricard-Mousnier, Brigitte | Thevenon, Julien | de Bellescize, Julitta | Catenoix, Hélène | Dorn, Thomas | Zenker, Martin | Müller-Schlüter, Karen | Brandt, Christian | Krey, Ilona | Polster, Tilman | Wolff, Markus | Balci, Meral | Rostasy, Kevin | Achaz, Guillaume | Zacher, Pia | Becher, Thomas | Cloppenborg, Thomas | Yuskaitis, Christopher | Weckhuysen, Sara | Poduri, Anna | Lemke, Johannes | Møller, S. | Baulac, Stéphanie
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PurposeTo define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathwayMethodsWe analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants.ResultsThe GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign.ConclusionOur data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.
